OBJECTIVE: Patients with fibromyalgia (FM) consistently have adrenal hyporesponsiveness and low dehydroepiandrosterone (DHEA) levels. DHEA is promoted for and used by patients with FM. We tested the efficacy and safety of DHEA supplementation in ameliorating the symptoms of FM. METHODS: In a double-blind crossover study, postmenopausal women with FM were randomized to DHEA supplementation (50 mg/day) or placebo for 3 months, with a one-month washout period in between. Patients were assessed monthly for well-being and pain and by medical evaluations at the beginning and the end of each treatment period. The primary outcome was well being; secondary outcomes were pain, fatigue, cognition, sexuality, functional impairment, depression, and anxiety. RESULTS: A total of 52 patients were randomized, 47 patients completed the DHEA treatment period, and 45 the placebo treatment period. After 3 months of treatment with 50 mg of DHEA, median DHEA sulfate blood levels had tripled, but there was no improvement in well-being, pain, fatigue, cognitive dysfunction, functional impairment, depression, or anxiety, nor in objective measurements made by physicians. Androgenic side effects (greasy skin, acne, and increased growth of body hair) were more common during the DHEA treatment period (p = 0.02). CONCLUSION: DHEA does not improve quality of life, pain, fatigue, cognitive function, mood, or functional impairment in FM.